Preparation of nanodiamond anchored on copper tannic acid as a heterogenous catalyst for synthesis of 1,4-benzodiazepines derivatives

In this research, a new and eco-friendly heterogeneous catalyst (ND@Tannicacid-Cu) was synthesized based on nanodiamond and copper tannic acid via esterification process. The as-prepared catalyst was characterized by Fourier transforms infrared spectroscopy (FT-IR), energy dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM), and X-ray diffraction (XRD) methods. The catalytic efficacy of the intended catalyst was examined by one-step three-component reaction of 1,4-benzodiazepine derivatives from a mixture of ortho-phenylenediamine, aromatic aldehydes, and dimedone under mild conditions. In all instances, corresponding 2,4-benzodiazepines derivatives were synthesized with high efficiency, short reaction time, straightforward work up procedure, no requirement for column-chromatography, and cost-effective catalyst. The heterogeneous catalyst was easily recycled using fillers, and it can be reused for eight cycles without significantly diminishing its performance.

be regarded as a highly effective means to attain this objective, as these reactions possess key attributes, such as the employment of eco-friendly solvents, reduced energy consumption, optimal utilization of atoms, expedited reaction times, and excellent efficacy 23 .Benzodiazepines are a category of sedative substances characterized by their molecular composition consisting of the amalgamation of a benzene ring and a diazepine ring.These compounds serve as essential intermediates for the production of heterocyclic compounds, such as oxadiazole 24 , triazole 25 , oxazine 26 , and furanodiazepines 27 .Furthermore, benzodiazepine derivatives have found wide-ranging use due to their therapeutic properties, such as anticonvulsants 28 , sedatives 29 , and antidepressants 30 .Various catalysts have been reported for benzodiazepine synthesis, such as CoFe 2 O 4 @GO-K22-Ni nanocomposite 31 , graphene oxide (GO) nanosheets 31 , palladium (Pd)-catalyzed approaches 32 , Fe 3 O 4 /f-MWCNT/Ni 2 B 33 , and etc.While these methods have demonstrated promise in benzodiazepine synthesis, it is imperative to acknowledge their associated limitations.Common issues that have been encountered include prolonged reaction times, low yields, challenges in catalyst separation, harsh reaction conditions, and high energy consumption.Recognizing these limitations, this study aims to address these shortcomings and propose an innovative approach that overcomes these challenges while ensuring efficient and sustainable benzodiazepine synthesis.Herein, we introduce a new and efficient heterogeneous catalyst, denoted as Nanodiamond@Tannic acid (ND@ tannic acid), which is functionalized with Cu nanoparticles for the first time 34,35 .The ND@Tannicacid-Cu catalyst was employed in the synthesis of 1,4-benzodiazepine derivatives.It can be easily separated from the reaction mixture through filtration and demonstrates the ability to be reused for at least eight cycles without experiencing a significant decrease in catalytic activity.Importantly, this nanocatalyst possesses intrinsic properties, such as eco-friendly, biocompatibility, recyclability, physiological inertness, and non-toxicity.

Materials and methods
All of the solvents, chemicals, and reagents were procured from Merck, Sigma, and Aldrich.The spherical detonation NDs were obtained from plasma chem company (Germany).Fourier transform infrared spectroscopy (FT-IR) was recorded on a Shimadzu IR-470 spectrometer by the KBr pellet.Melting points were measured on an Electrothermal 9100 device.1H nuclear magnetic resonance (NMR) spectra were recorded on a Bruker DRX-500 Avance spectrometer at 500 (Figures.S1-S5).SEM images were acquired using a Sigma-Zeiss microscope equipped with an attached camera.The nanocatalyst underwent elemental analysis through the utilization of energy-dispersive X-ray (EDX) analysis, which was recorded via the Numerix DXP-X10P.

Preparation of ND@Tannicacid-Cu catalyst
In order to synthesize carboxylate nanodiamonds (ND), 1.00 g of diamond nanoparticles (NPs) was placed in the oven at a temperature of 450 °C for 5 h at a rate of 1 °C/min.In the process of esterification of nanodiamond functionalized with tannic acid (Fig. 1), 10 mg of nanodiamond functionalized with carboxylic acid was mixed in 10 mL of deionized water and then stirred at 80 °C for 5 h.Afterward, HCl (1 M) was added to the reaction until the pH value reached 4.7.After that, 20 mg of tannic acid was added drop-wise to the above reaction mixture.The resultant mixture was stirred for 24 h at 80 °C.Finally, the prepared nanoparticle was filtered and washed several times with deionized water.It was dried at 50 °C for 24 h.In the final step, 1 mmol (0.187 g) of Cu(NO 3 ) 2 and 200 mg of the ND@Tannicacid were separately dissolved in 10 mL of ethanol and subsequently added together slowly.The resulting mixture was then allowed to react for 6 h at ambient temperature.The produced catalyst was washed several times with ethanol and water and dried at 50 °C for 24 h (Fig. 1).

General procedure for the synthesis of 1,4-benzodiazepin derivatives
In a flask, 1 mmol of ortho-phenylenediamine (0.108 g), 1 mmol of dimedone (0.140 g), 1 mmol of benzaldehyde derivatives, and 10 mg of the ND@Tannicacid-Cu was dissolved in 5 mL of EtOH and stirred at 50 °C (Fig. 2).The completion of the reaction was monitored by thin layer chromatography (TLC).After that, the catalyst was easily separated by filtration.The pure product obtained from the reaction mixture was recrystallized by hot ethanol.All of the products were known compounds, which were identified through the characterization of their melting points as provided in Table 3.This identification was conducted by comparing the melting points of the products with those of authentic literature samples.In certain instances, the identification was further supported by analyzing the 1 H-NMR spectral data of the compounds.

FT-IR analysis
The ND@Tannicacid-Cu catalyst was successfully prepared and characterized by several techniques.The FT-IR spectra of (a) ND, (b) ND-COOH, (c) ND@Tannicacid, and (d) ND@Tannicacid-Cu catalyst are shown in Fig. 3.As depicted in Fig. 3a, the diamond lattice vibration observed at a wavenumber of 1332 cm −1 is associated with the first order Raman band and is usually not observed in the FT-IR.Nevertheless, this particular band has been observed in multiple studies, where its presence has been attributed to the disruption of symmetry in the diamond C-C bond near the surface caused by the surface groups.Moreover, the broad absorption band observed within the frequency range of 1720-1780 cm −1 can be attributed to the stretching modes of C = O bonds, which are induced by oxidation treatments that are employed during the cleaning process of non-diamond carbon from the NDs.Finally, the observation of C-H bending modes around 1460 cm −1 is made in the presence of hydrogenated groups on the surface of the NDs.In Fig. 3b, the absorption spectrum at 1720 cm −1 exhibits the vibrational stretching of the carbonyl linkage (C = O) 36 .The bands observed at 2917 cm −1 are attributed to the asymmetric and symmetric stretching vibrations of C-H bonds 37 .Furthermore, the strong peak that appears at 3424 cm −1 describes the asymmetric stretching vibration of the O-H group.All of these various explanations contribute to the phenomenon of diamond nanoparticle carboxylation.Figure 3c depicts the FT-IR spectrum of the ND@Tannicacid.The strong peak at 1745 cm −1 demonstrates the stretching vibration of the carbonyl group of ester 38 .Besides, the absorption band in the region of 3223 cm −1 is related to the symmetric and asymmetric stretching vibration of the aromatic C-H bond, which is the reason for the interaction between tannic acid and nanodiamonds (Fig. 3d).

Morphological observations
The morphology and size details of the as-prepared catalyst were investigated by SEM measurements, as illustrated in Fig. 4. The SEM images of the ND@Tannicacid-Cu nanocatalyst demonstrate that the particle shape is spherical and the particle size distribution is uniform with an average size of 35 ± 10 nm.

EDX and elemental mapping analyses
The findings from the analysis of the ND@Tannicacid-Cu nanoparticles, utilizing EDX-mapping, are visually presented in Fig. 5 Immobilizing of copper (Cu) onto tannic acid.The process of immobilizing copper (Cu) onto tannic acid occurs in two distinct steps.Firstly, diamond nanoparticles are carboxylated through a heat-induced reaction, followed by the esterification of these functionalized carboxylated nanoparticles with tannic acid.
In the final step, copper (Cu) is securely anchored to the tannic acid.ND@Tannicacid-Cu proves to be highly effective for the synthesis of 1,4-benzodiazepine derivatives.catalyst.It can be concluded that the elemental mapping of components in the ND@Tannicacid-Cu catalyst conforms to the percentages reported by the EDX analysis.

Catalytic performance of ND@Tannicacid-Cu catalyst
We conducted optimization on the catalytic efficacy of various catalysts, such as ND, ND-OH, ND-COOH, Tannic acid, Cu(NO 3 ) 2 , ND@Cu, ND@Tannicacid, and ND@Tannicacid-Cu (Table 1, Entries 1-8).These catalysts were utilized in a one-pot three component reaction involving o-phenylenediamine 1 (1 mmol, 0.108 g), diamond 2 (1 mmol, 0.140 g), and 4-nitrobenzaldehyde 3 (1 mmol) in EtOH at 50 °C as a model reaction (Table 1).Afterward, the effects of temperature on the reaction efficiency were investigated (Table 1, Entries 9-12).When www.nature.com/scientificreports/ the reaction reached its completion under ambient conditions, an observation of 70% yields was made.As the temperature escalated, there was a corresponding rise in the reaction yields.Subsequently, we conducted an examination on the impacts of different solvents in the reaction (Entries 16-13).Drawing on the data acquired from Table 1, it can be deduced that EtOH solvent is the optimal choice for obtaining the highest yields in the reaction.Finally, we studied the effects of the amount of catalyst on the reaction (Entries 17-20).It has been determined that the utilization of 10 mg of ND@Tannicacid-Cu nanocatalyst is adequate for the purpose of accomplishing the reaction within 10 min, resulting in a yield of 98% in 5 mL of EtOH at reflux temperature.

Comparison of different Ar group effects in the presence of the ND@Tannicacid-Cu
In Table 2, a comparative analysis was conducted between the current study and previous reports pertaining to the synthesis of 4d.The outcomes undeniably showcase the advantageous nature of the current study in terms of time efficiency, energy conservation, and substantial product yields.Furthermore, the potential for nanocatalyst reusability is also evident.With great pleasure, it was noted that a remarkable level of effectiveness, reaching a maximum of 96%, could be attained for 10 min.This resulted in the production of a turnover number (TON) of 160 × 10 3 and a turnover frequency (TOF) of 941 × 10 3 (Table 2, Entry 4).

Comparative studies
After the optimization of the reaction parameters, an investigation was conducted to ascertain the breadth and universality of these optimized conditions in the synthesis of a diverse range of 1,4-benzodiazepine derivatives.
The results presented in Table 3 demonstrate that all the desired products were attained with excellent efficiency following the appropriate duration of the reaction.

Suggested reaction mechanism
Based on the results of recent studies, we presented a proposed mechanism for the synthesis of benzodiazepines using ND@Tannicacid-Cu catalyst (Fig. 7), the interaction between the oxygen atom of dimedone and the active sites on the surface of the catalyst occurs through the utilization of lone pairs of electrons.Additionally, the carbonyl group of dimedone is attacked by the NH 2 group of ortho-phenylenediamine, resulting in the elimination of H 2 O and the formation of the intermediate imine 4. Subsequently, 1,3-hydrogen shift takes place, leading to the creation of the tautomeric enamine 5.The NH 2 group of the enamine intermediate 5 would subsequently engage in a reaction with the activated carbonyl group of the aromatic aldehyde 6 in order to produce the corresponding imine 7. The imine 7 would then experience an intramolecular cyclization, resulting in the formation of the desired benzodiazepine ring with a seven-membered structure.

Recyclability of ND@Tannicacid-Cu nanocatalyst
The reusability of the catalyst is one of the main advantages, allowing it to be used in commercial applications.
Thereafter, the reusability of ND@Tannicacid-Cu nanocatalyst was investigated in model reactions (Fig. 8).After  www.nature.com/scientificreports/ the completion of the reaction, the nanocatalyst was filtered and washed several times with diethyl ether, dried and reused in subsequent reactions.It was observed that the catalyst could be reused at least 8 times without significant loss in product yields.

Conclusions
In summary, functionalization of diamond nanoparticles with copper tannic acid has been synthesized by esterification process and completely characterized by several analysis.Afterwards, the catalytic activity of the ND@ Tannicacid-Cu in the synthesis of 1,4 benzodiazepine derivatives was investigated.The products were obtained in excellent yield under mild reaction conditions and compatible with green chemistry.The as-prepared nanocatalyst was easily filtered and used for eight times without significant decrease in its catalytic activity.This is the first report on the design, synthesis, and characterization of the present nanocatalyst in synthesis of 1,4-benzodiazepines derivatives.
Figure1.Immobilizing of copper (Cu) onto tannic acid.The process of immobilizing copper (Cu) onto tannic acid occurs in two distinct steps.Firstly, diamond nanoparticles are carboxylated through a heat-induced reaction, followed by the esterification of these functionalized carboxylated nanoparticles with tannic acid.In the final step, copper (Cu) is securely anchored to the tannic acid.ND@Tannicacid-Cu proves to be highly effective for the synthesis of 1,4-benzodiazepine derivatives.

Figure 2 .
Figure 2. Synthesis process of 1,4-benzodiazepine derivatives in the presence of synthesized catalyst.

Figure 4 .
Figure 4. SEM images of the ND@Tannicacid-Cu catalyst with different scale bars.

Table 1 .
Optimizing of the reaction conditions in the synthesis of 1,4-benzodiazepin derivatives.

Table 2 .
Comparison of some catalyst's effects with ND@Tannicacid-Cu on the model reaction.